Esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones

ABSTRACT

A compound of structural Formula (I) or pharmaceutically acceptable salts thereof wherein: R is --C(O)--R 1 , --PO 3  ═ or --P(O)(OH) 2  ; R 1  is C 1-6  alkyl, --N(R 4 ) 2 , C 1-6  alkyl-N(R 4 ) 2 , --phenyl--N(R 4 ) 2 , --phenyl-NHC(O)CH 2  NH 2 , --C 2  H 4  -morpholinyl, pyridinyl, C 1-6  alkyl-OH, C 1-6  alkyl-OCH 3 , C 1-6  alkyl C(O)CH 3 , --O--C 1-6  alkyl-OCH 3 , C 0-3  alkyl-piperazinyl (optionally substituted with C 1-3  alkyl), imidazolyl, C 1-6  alkyl-COOH, --C(CH 2  OH) 2  CH 3  ; R 2  and R 3  are independently selected from hydrogen or F except at least one of R 2  or R 3  is F; R 4  are independently selected from hydrogen or C 1-6  alkyl. The compounds are water soluble and are useful antimicrobial agents, effective against a number of human veterinary pathogens, including multiply-resistant staphylococci, enterococci and streptococci, as well as anerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis.

This application is a 371 of PCT/US94/10582 wich is acontinuation-in-part of U.S. Ser. No. 08/155,988 filed 22 Nov. 1993,abandoned.

BACKGROUND OF THE INVENTION

The subject invention discloses carboxylic and phosphate esters ofsubstituted-hydroxyacetyl piperazine phenyl oxazolidinones. Thecompounds and their salts are water soluble which makes themparticularly useful for IV and oral administration for the treatment ofmicrobial infections. The compounds are effective against a number ofhuman and veterinary pathogens, including multiply-resistantstaphylococci, enterococci and streptococci, as well as anerobicorganisms such as bacteroides and clostridia species, and acid-fastorganisms such as Mycobacterium tuberculosis. The compounds areparticularly useful because they are effective against the latterorganism wich is known to be responsible for infections in persons withAIDS. Information Disclosure Statement

U.S. Pat. Nos. 5,164,510 and related 5,225,565 and 5,182,403 discloses5'indolinyl-5β-amidomethyloxazolidinones, 3-(fused-ringsubstituted)phenyl-5β-amidomethyloxazolidinones, and 3-(nitrogensubstituted)phenyl-5β-amidomethyloxazolidiones wich are useful asantibacterial agents.

PCT/US93/03570 discloses hydroxyacetyl diazene phenyl oxazolidinoessimilar to the subject compounds except that the subject compounds aresubstituted with carboxylic and phosphate esters (i.e., R is --C(O)--R₁,--PO₃.sup.═ or --P(O)(OH)₂) and are water soluble.

Other references disclosing various oxazolidinones include U.S. Pat.Nos. 4,801,600, 4,921,869, Gregory W. A., et al., J. Med. Chem., 32,1673-81 (1989); Gregory W. A., et al., J. Med. Chem., 33, 2569-78(1990); Wang C., et al., Tetrahedron, 45, 1323-26 (1989); and Brittelli,et al., J. Med. Chem., 35, 1156 (1992).

European Patent Publication 352,781 discloses phenyl and pyridylsubstituted phenyl oxozolidiones.

European Patent Publication 316,594 discloses 3-substituted styryloxozolidiones.

European Patent Publication 312,000 discloses phenylmethyl andpyridinylmethyl substituted phenyl oxazolidinones.

SUMMARY OF THE INVENTION

In one aspect, the subject invention is a compound of structural FormulaI: ##STR1## or pharmaceutailly acceptable salts thereof wherein:

R is --C(O)--R¹, --PO₃.sup.═ or --P(O)(OH)₂ ;

R¹ is C₁₋₆ alkyl, --N(R⁴)₂, C₁₋₆ alkyl-N(R⁴)₂, -phenyl-N(R⁴)₂,-phenyl-NHC(O)CH₂ NH₂, --C₂ H₄ -morpholinyl, pyridinyl, C₁₋₆ alkyl-OH,C₁₋₆ alkyl-OCH₃, C₁₋₆ alkyl C(O)CH₃, --O--C₁₋₆ alkyl-OCH₃, C₀₋₃alkyl-piperazinyl (optionally substituted with C₁₋₃ alkyl), imidazolyl,C₁₋₆ alkyl-COOH, --C(CH₂ OH)₂ CH₃ ;

R² and R³ are independently selected from hydrogen or F, except at leastone of R² or R³ is F;

R⁴ are independently selected from hydrogen or C₁₋₆ alkyl.

Preferred compounds of the subject invention are where R is --C(O)--R¹and R¹ is --CH₃, --CH₂ N(CH₃)₂, --C₂ H₄ -morpholinyl or --CH₂ OH. Evenmore preferred is where the compound is an optically pure enantiomerhaving the S- configuration at C5 of the oxazolidinone ring. Morepreferable is where one of R² and R³ is F and the other is hydrogen.

In another aspect, the subject invention is directed toward a method fortreating microbial infections in warm blooded animals by administeringto a warm blooded animal in need thereof an effective amount of acompound of Formula I as described above. Preferably, the compound isadministered in an amount of from about 0.1 to about 100 mg/kg of bodyweight/day, more preferably, from about 3.0 to about 50 mg/kg of bodyweight/day.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses carboxylic and phosphate esters ofsubstituted-hydroxyacetyl piperazinyl phenyl oxazolidinones ofstructural Formula I as defined above. The compounds are usefulantimicrobial agents, effective against a number of human and veterinarypathogens, including multiply-resistant staphylococci, enterococci andstreptococci, as well as anaerobic organisms such as bacteroides andclostridia species, and acid-fast bacteria such as Mycobacteriumtuberculosis. The compounds are designed to be aqueous soluble such thatthey can be administered by intravenous or oral means.

With respect to the above definition, C₁₋₆ alkyl is methyl, ethyl,propyl, butyl, pentyl, hexyl and isomeric forms thereof.

Pharmaceutically acceptable salts means salts useful for administeringthe compounds of this invention and include hydrochloride, hydrobromide,hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate,maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethylsulfonate, fumarate, sodium or potassium, ammonioum salt and the like.These salts may be in hydrated form.

The most preferred compounds of the series would be prepared as theoptically pure enantiomers having the (S)-configuration at C5 of theoxazolidinone ring. More preferably the compounds have only one ofeither R² and R³ as fluorine. The compounds of this invention have anaqueous solubility of greater than 1 mg/ml, more preferably, greaterthan 4 mg/ml.

Optically pure material could be obtained either by one of a number ofasymmetric syntheses or alternatively by reolution from a racemicmixture by selective crystallization of a salt form, for example,intermediate amine 12 (as described in Example 1) with an appropriateoptically active acid such as dibenzoyl tartrate or 10-camphorsulfonicacid, followed by treatment with base to afford the optically pureamine.

Commercially available difluoronitrobenzene is treated with excesspiperazine to afford a displacement product. Reduction of the nitrogroup with the ammonium formate-Pd/C regent system or hydrogen-Pd/Caffords an aniline derivative. Protection of this aniline derivativeaffords a bis-(benzyloxy carbonyl) (CBZ) derivative which is treatedwith nBuLi in THF or ether at -78° to -15° C., then R-glycidyl butyrateis added, and the mixture stirred overnight at 20° C., to give opticallyactive 5-(R)-hydroxy methyl oxazolidinone. Mesylation of 5-(R)-hydroxymethyl oxazolidinone under classical conditions affordes a mesylatewhich undergoes smooth displacement with sodium azide to form an azide.Reduction of the azide by hydrogenation over Pd/C gives an amine whichcan be acylated in situ with acetic anhydride and pyridine to afforded aCBZ-protected oxazolidinone intermediate,(S)-N-3-((3-fluoro-4-(4-(carbobenzyloxy)-1-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide.More preferred, the aminomethyloxazolidinone is prepared by displacementof the mesylate with potassium phthalimide to give a phthalimide.Treatment of this phthalimide with aqueous methylamine gives the amine.

Deprotection of the N-carbobenzyloxy with Pd/C and hydrogen afforded thekey intermediate for analog preparation,(S)-N-3-((3-fluoro-4-(1-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide(22).

These compounds are useful for treatment of microbial infections inhumans and other warm blooded animals, under both parenteral, topicaland oral administration.

The pharmaceutical compositions of this invention may be prepared bycombining the compounds of Formula I of this invention with a solid orliquid pharmaceutically acceptable carrier and, optionally, withpharmaceutically acceptable adjuvants and excipients emplyoying standardand conventional techniques. Solid form compositions include powders,tablets, dispersible granules, capsules, cachets and suppositories. Asolid carrier can be at least one substance which may also function as adiluent, flavoring agent, solubilizer, lubricant, suspending agent,binder, tablet disintegrating agent, and encapsulating agent. Inertsolid carriers include magnesium carbonate, magnesium stearate, talc,sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials,low melting wax, cocoa butter, and the like. Liquid form compositionsinclude solutions, suspensions and emulsions. For example, there may beprovided solutions of the compounds of this invention dissolved in waterand water-propylene glycol and water-polyethylene glycol systems,optionally containing suitable conventional coloring agents, flavoringagents, stabilizers and thickening agents.

Preferably, the pharmaceutical composition is provided employingconventional techniques in unit dosage form containing effective orappropriate amounts of the active component, that is, the compound ofFormula I according to this invention.

The quantity of active component, that is the compound of Formula Iaccording to this invention, in the pharmaceutical composition and unitdosage form thereof may be varied or adjusted widely depending upon theparticular application, the potency of the particular compound, thedesired concentration. Generally, the quantity of active component willrange between 0.5% to 90% by weight of the composition.

In therapeutic use for treating, or combatting, bacterial infections inwarm-blooded animals, the compounds or pharmaceutical compositionsthereof will be administered orally and/or parenterally at a dosage toobtain and maintain a concentration, that is, an amount, or blood-levelof active component in the animal undergoing treatment which will beantibacterially effective. Generally, such antibacterially effectiveamount of dosage of active component will be in the range of about 0.1to about 100, more preferably about 3.0 to about 50 mg/kg of bodyweight/day. It is to be understood that the dosages may vary dependingupon the requirements of the patient, the severity of the bacterialinfection being treated, and the particular compound being used. Also,it is to be understood that the initial dosage administered may beincreased beyond the above upper level in order to rapidly achieve thedesired blood-level or the initial dosage may be smaller than theoptimum and the daily dosage may be progressively increased during thecourse of treatment depending on the particular situation. If desired,the daily dose may also be divided into multiple doses foradministration, e.g., two tofour times per day.

The compounds of Formula I according to this invention are administeredparenterally, i.e., by injection, for example, by intravenous injectionor by other parenteral routes of administration. Pharmaceuticalcompositions for parenteral administration will generally contain apharmaceutically acceptable amount of the compound according to FormulaI as a soluble salt (acid addition salt or base salt) dissolved in apharmaceutically acceptable liquid carrier such as, for example,water-for-injection and a buffer to provide a suitably buffered isotonicsolution, for example, having a pH of about 3-7. Suitable buffereingagents include, for example, trisodium orthophosphate, sodiumbicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine andL(+)-arginine to name but a few representative buffering agents. Thecompound according to Formula I generally will be dissolved in thecarrier in an amount sufficient to provide a pharmaceutically acceptableinjectable concentration in the range of about 1 mg/ml to about 400mg/ml of solution. The resulting liquid pharmaceutical composition willbe adminsitered so as to obtain the above-mentioned antibacteriallyeffective amount of dosage. The compounds of Formula I according to thisinvention, due to their aqueous solubility, are advantageouslyadministered orally in solid and liquid dosage forms.

Antimicrobial activity was tested in vivo using the Murine Assayprocedure. Groups of female mice (six mice of 18-20 grams each) wereinjected intraperitoneally with bacteria which were thawed just prior touse and suspended in brain heart infusion with 4% brewers yeast UC9213(Staphylococcus aureus) or brain heart infusion (Streptococcus species).Antibiotic treatment at six dose levels per drug was administered onehour and five hours after infection by either oral intubation orsubcutaneous ("subcut.") routes. Survival was observed daily for sixdays. ED₅₀ values based on mortality ratios were calculated using probitanalysis. The subject compounds were compared against a well-knownantimicobial (Vancomycin) as a control. The data are shown in Table 1.

                  TABLE 1    ______________________________________    In Vivo Activity of Examples                      VANCOMYCIN ED.sub.50    Example ED.sub.50 mg/kg                      mg/kg (subcut.) ROUTE    ______________________________________    1       5/4       2               oral/subcut.    2       9/15      5               oral/subcut.    3       16/8      8               oral/subcut.    4       2/2       2               oral/subcut.    5       7/5       5               oral/subcut.    6       2/2       2               oral/subcut.    7       >20/1     6               oral/subcut.    8       10/6      5               oral/subcut.    9       2/3       1               oral/subcut.    10      1/2       3               oral/subcut.    11      8/8       4               oral/subcut.    12      12/>20    5               oral/subcut.    13      >20/>20   4               oral/subcut.    14      3         2               oral    16      4         2               oral    17      5/2       2/1             oral/subcut.    18      14/>20    10              oral/subcut.    20      6/4       6               oral/subcut.    21      8/13      3               oral/subcut.    22      >18/4     3               oral/subcut.    23      2/1       3               oral/subcut.    24      1         2               oral    25      8/15      6               oral/subcut.    26      6/3       2               oral/subcut.    27      6         5               oral    29      9         4               oral    ______________________________________

In Table 1 the compound structures of each of the Examples are shown inTable 2 as follows:

                  TABLE 2    ______________________________________    Example   R                   R.sup.2                                        R.sup.3    ______________________________________    1         C(O)-C.sub.2 H.sub.4 -morpholinyl                                  H     F    2         C(O)-3-pyridinyl    H     F    3         C(O)-3-pyridinyl    F     F    4         C(O)-1-imidazolyl   H     F    5         C(O)-1-imidazolyl   F     F    6         C(O)OC.sub.2 H.sub.4 OCH.sub.3                                  H     F    7         C(O)p-N(CH.sub.3).sub.2 Ph                                  H     F    8         C(O)p-N(CH.sub.3).sub.2 Ph                                  F     F    9         C(O)CH.sub.2 N(CH.sub.3).sub.2                                  H     F    10        C(O)CH.sub.2 N(CH.sub.3).sub.2                                  F     F    11        C(O)(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                  H     F    12        C(O)(CH.sub.2).sub.3 N(CH.sub.3).sub.2                                  H     F    13        C(O)CH.sub.2 -4-methyl-1-piperazinyl                                  H     F    14        C(O)CH.sub.3        F     F    15        C(O)C.sub.2 H.sub.4 C(O)OH                                  F     F    16        C(O)C.sub.2 H.sub.4 C(O)O.sup.- Na.sup.+                                  F     F    17        C(O)C.sub.2 H.sub.4 C(O)OH                                  H     F    18        C(O)C.sub.2 H.sub.4 C(O)CH.sub.3                                  F     F    19        C(O)C.sub.2 H.sub.4 C(O)CH.sub.3                                  H     F    20        P(O)(OH).sub.2      H     F    21        C(O)p-NH.sub.2 Ph   H     F    22        C(O)C(CH.sub.3)(CH.sub.2 OH).sub.2                                  H     F    23        C(O)CH.sub.2 OH     H     F    24        C(O)CH.sub.2 OH     F     F    25        C(O)CH.sub.2 OCH.sub.3                                  H     F    26        C(O)C.sub.2 H.sub.4 -4-morpholinyl                                  F     F    27        C(O)CH.sub.2 -4-morpholinyl                                  H     F    28        C(O)p[NHC(O)CH.sub.2 N(CH.sub.3).sub.2 ]Ph                                  H     F    29        C(O)p(-NHC(O)CH.sub.2 NH.sub.2)Ph                                  H     F    30        C(O)CH.sub.3        H     F    ______________________________________

EXAMPLE 1 3-(4-Morpholinyl)propionic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylester, (S)

A 3 liter 3-neck flask fitted with a mechanical stirrer, thermometer andnitrogen inlet was charged with 45.789 g of(S)-N-[[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideand 1.3 liters of CH₂ Cl. The mixture was cooled in an ice bath and 38ml of triethylamine was added uner nitrogen, then 28 ml ofbenzyloxyacetyl chloride was added via an addition funnel over 35minutes, and the ice bath removed. After 1.5 hours, 500 ml of water wasadded, the layers were separated, and the organic phase washed with 500ml of water. The aqueous layers were extracted with methylene chlorideand the combined organic layers dried and concentrated which caused theprecipitation of product. This was collected, filtered and washed withmethylene chloride to yield 57.48 g of pure(S)-N-[[3-fluoro-4-(4-(benzyloxyacetyl)-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.

A 5 L flask was charged with 29.04 g of this product and 2 L of 33%methylene chloride/methanol (v/v) and was evacuated and filled withnitrogen. The 8.1 g of 10% palladium/carbon was added as a slurry in 50ml of methylene chloride/methanol (1:2, v/v), and the flask evacuatedand filled with nitrogen, the evacuated and filled with hydrogen viaballoon. The reaction mixture was stirred over night, the flackevacuated and filled with nitrogen, and the mixture filtered overdiatomaceous earth, and the filter pad washed with 33% methylenechloride/methanol (v/v) and concentrated to give a white solid. Thissolid was purified by column chromatography (silica gel packed inchloroform), and gradient eluted with 3-11% methanol/chloroform to givea white foamy solid. This solid was take up in 10% methanol/ethyacetate,and concentrated to dryness several times to give an amorphous whitesolid, 20.448 g (86.5%) of(S)-N-[[[3-fluoro-4-(4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,mp 17 6°-177° C., (hereinafter, referred to as "Intermediate")

The Intermediate, 421 mg (1.07 mmol) was dissolved in 21 mL of pyridine.To this solution was added 13 mg of DMAP, 268 mg (2.14 mmol) of3-morpholinepropionic acid and 411 mg (2.14 mmol) of1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. Thereaction was allowed to stir at room temperature, under N₂ for 15 hours.After this time, the reaction was complete and was concentrated invacuo. The crude product was purified twice by silica gel chromatography(30 g of silica gel, eluted with 0.5-4% MeOH/CHCl₃). After concentrationof pure fractions, 372 mg (65%) of the title compound was recovered as aglassy, white solid. mp: 87°-90° C. Auqeous solubility (pH 7, phosphatebuffer) was 36 mg/ml.

EXAMPLE 2 Nicotinic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

A mixture of 251 mg (0.637 mmol) of the Intermediate form Ex. 1, 258 mg(1.35 mmol) of 1-ethyl-3-(3-dimethylamino) propylcarbodiimide, 169 mg(1.37 mmol) nicotinic acid and a catalytic amount of4-dimethylaminopyridine in 5.0 ml of pyridine was stirred for 24 hoursat room temperature. After this time, the mixture was concentrated invacuo and the obtained crude was taken up in methylene chloride andplaced upon a 23.5 cm×2.5 cm 40-63 μ silica column. The column waseluted with ethylacetate, 5% methanol/ethylacetate, 10%methanol/ethylacetate, and 20% methanol/ethylacetate (250 ml each). Theappropriate fractions were pooled to provide 300 mg (94%) of the titlecompound as white foamy solid. The solid changed to a glasssy oil at80°-85° C. then melted at 173°-175° C. Aqueous solubility (pH 7,phosphate buffer) was 0.3 mg/ml but a salt version should have highersolubility.

EXAMPLE 3 Nicotinic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-6

The subject compound was prepared from(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(preparation descrbied in Ex. 15) in 77% yield (mp=213°-214° C.)following the same procedure as for Example 2. Aqueous solubility (pH 7,phosphate buffer) was 0.05 mg/ml but salt version should have highersolubiltiy.

EXAMPLE 4 1H-imidazole-1-carboxylic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

A mixture of 246 mg (0.624 mmol) of the Intermediate from Ex. 1 and 304mg (1.875 mmol) of carbonyl diimidazole in 10 ml of tetrahydrofuran wasstirred over night. The resulting precipitate was filtered away from thesolvent, washed and dried to provide 251 mg (82% yield) of the subjectcompound; (mp=188°-189° C.) Aqueous solubility (pH 7, phosphate buffer)was 1.4 mg/ml.

EXAMPLE 5 1H-imidazole-1-carboxylic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

The subject compound was prepared from(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(preparation described in Ex. 15) in 82% yield (mp=199°-200° C.)following the same procedure as for Example 4.

EXAMPLE 6 Carbonic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester-2-methoxyethyl ester, (S)

To a solution of 175 mg (0.444 mmol) of the Intermediate from Ex. 1 in5.0 ml methylene chloride at 0° C. under nitrogen was added 0.25 ml(1.79 mmol) triethyamine followed by 129 mg (0.931 mmol) 2-methoxyethylchloroformate as a solution in 0.5 ml methylene chloride. The mixturewas allowed to slowly warm to room temperature over night. Afterstirring over night, 5 ml of 1N HCl was added and the resulting solventlayers were separted. The aqueous layer was extracted with methylenechloride (2×5 ml). The combined organic layers were washed with brineand dried (MgSO₄) then concentrated to an oil. The crude was placed upona 24 cm×2.5 cm 40-63 μ silica column. The column was eluted withethylacetate (300 ml), 5% methanol/ethylacetate, 10%methanol/ethylacetate, 15% methanol/ethylacetate, and 20%methanol/ethylacetate (250 ml each). The appropriate fractions werepooled to provide 170 mg (77% yield) of the subject compound as a foamysolid. Part of the solid was crystallized from boiling ethylacetate toprovide 65 mg (65% recovery) of the subject compound as a crystallinesolid (mp=149°-151° C.). Aqueous solubility (pH 7, phosphate buffer) was2.9 mg/ml.

EXAMPLE 7 4-dimethylaminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

A mixture of 251 mg (0.637 mmol) of the Intermediate from Ex. 1, 181 mg(0.944 mmol) of 1-ethyl-3-(3-dimethylamino) propylcarbodiimide, 181 mg(1.10 mmol) 4-dimethylaminobenzoic acid and a catalytic amount of4-dimethylamino pyridine in 3.0 ml of pyridine was stirred over night atroom temperature. After this time, another 151 mg (0.914 mmol) of4-dimethylaminobenzoic acid was added and stirring continued over night.After this time another 89 mg (0.464 mmol) of 1-ethyl-3-(3-dimethylaminopropylcarbodiimide was added to the mixture. The mixture was stirred for5 days at room temperature and then warmed in a 50° C. oil bath for onehour. The incomplete reaction mixture was then concentrated in vacuo.The obtained crude was taken up in methylene chloride and placed upon a24 cm×2.5 cm 40-63 μ silica column. The column was eluted withethylacetate (250 ml), 10% methanol/ethylacetate (500 ml), 15%methanol/ethylacetate (250 ml), and 20% methanol/ethylacetate (500 ml).The appropriate fractions were pooled to provide 95 mg (41%) of a whitesolid which was triturated in ethylacetate to provide 75 mg (32%) of thesubject compound as a white solid (mp=210°-211° C.). Aqueous solubility(pH 7, phosphate buffer) was 0.01 mg/ml but salt version should havehigher solubility.

EXAMPLE 8 4-dimethylaminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

The subject compound was prepared from(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(preparation described in Ex. 15) in 59% yield (mp=199°-202° C.)following the procedure used for Example 7. Aqueous solubility (pH 7,phosphate buffer) was 0.01 mg/ml but salt version should have highersolubility.

EXAMPLE 9 Glycine, N,N-dimethyl-,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

The Intermediate from Ex. 1 (250 mg, 0.634 mmol) was dissolved into 8 mlof dry pyridine and ethyl-3-(3-dimethylamino propyl carbodiimidehydrochloride (243 mg, 1.27 mmol), DMAP (16 mg, 0.127 mmol) andN,N-dimethylglycine (131 mg, 1.27 mmol) was added. The mixture wasstirred under N₂ at ambient temperature for 18 hours. After this timethe solvent was removed under reduced pressure to give a gummy residue.The residue was dissolved into CH₂ Cl₂, washed with water and brine. Theorganic phase was separtated and dried over anhydrous Na₂ SO₄. Thesolution was filtered and concentrated to give a solid that was purifiedby recrystallization from CH₂ Cl₂ /Et₂ O. Isolated 220 mg of the subjectcompound as a white solid. mp=158°-159° C. Aqueous solubility (pH 7,phosphate buffer) was 150 mg/ml.

EXAMPLE 10 Glycine, N,N-dimethyl-,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

This material was prepared in the same manner as Example 9, but startingwith(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(preparation described in Ex. 15), mp=171°-172° C. Aqueous solubility(pH 7, phosphate buffer) was 4.2 mg/ml.

EXAMPLE 11 3-(Dimethylamino)propanoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

Methyl 3-(dimethylamino)propionate (2.0 g, 15.2 mmol) was hydrolyzed tothe acid by treatment with aqueous NaOH (18.2 mmol, 1.0N solution) atreflux for 2 hours. The solution was cooled to 0° C. via an ice-bath andtreated with 1.0N HCl (18.2 mmol). The solution was lyophilized to givea waxy solid that was used without any fruther purification.

The Intermediate from Ex. 1 (400 mg, 1.02 mmol) was dissolved into 10 mlof dry pyridine and the solution was treated with3-(dimethylamino)propanoic acid (crude material, 239 mg, 2.04 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (341 mg, 2.04mmol) and DMAP (25 mg, 0.204 mmol). The mixture was stirred at ambienttemperature under N₂ for 2.5 days. After this time the reaction mixturewas concentrated under reduced pressure to give a solid residue. Theresidue was slurried into CH₂ Cl₂ followed by washing with with waterand brine. The clear organic phase was separted and dried over anhydrousNa₂ SO₄. The dried solution was filtered and concentrated to a gum thatwas purified by recrystallization from CH₂ Cl₂ /Et₂ O. Isolated 296 mgof the desired product as a dull white solid. mp=136°-137° C.

EXAMPLE 12 4-(Dimethylamino)butanoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

The Intermediate from Ex. 1 (400 mg, 1.01 mmol) was dissolved into 10 mlof dry pyridine and the solution was treated with4-(dimethylamino)butyric acid hydrochloride (341 mg, 2.03 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide (389 mg, 2.03 mmol) andDMAP (248 mg, 2.03 mmol). The mixture was stirred at ambient temperatureunder N₂ for 40 hours. After this time the reaction mixture wasconcentrated under reduced pressure to give a gummy residue. The residuewas dissolved into CH₂ Cl₂ followed by washing with water and brine. Theorganic phase was separted and dried over anhydrous Na₂ SO₄. Filteredand concentrated to give a glassy residue that was purified byrecrystalliztion from CH₂ Cl₂ /Et₂ O. Isolated 178 mg of the desiredproduct as a white solid. mp=69°-71° C. Aqueous solubility (pH 7,phosphate buffer) was 34.6 mg/ml.

EXAMPLE 13 (4-Methyl-1-piperazinyl)acetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

The intermediate from Ex. 1 (400 mg, 1.01 mmol) was dissolved into 12 mlof dry CH₂ Cl₂ and the solution was cooled to 0° C. via an ice-bath.Next dry pyridine (92 mg, 1.16 mmol) was added followed by chloroacetylchloride (131 mg, 1.16 mmol) dropwise via syringe. After 30 minutes themixture was heated to a gentle reflux for 1 hour. The reaction wascooled and poured into a separatory funnel along with additional CH₂Cl₂. The solution was washed with 1% aqueous HCl, water and brine. Theorganic phase was dried over anhydrous Na₂ SO₄. Filtered andconcentrated to a foam that was purified by recrystallization from CH₂Cl₂ /Et₂ O. Isolated 407 mg of the intermediate chloroacetyl ester.mp=173°-174° C.

This chloracetyl ester intermediate (303 mg, 0.643 mmol) was dissolvedinto 7 ml of dry CH₃ CN and the solution was cooled to 0° C. via anice-bath. Next N-methylpiperazine (258 mg, 2.57 mmol) was added and themixture was stirred at 0° C. for 1 hour followed by warming to roomtemperature for 3 hours. After this time TLC showed starting materialwas consumed. The reaction mixture was poured into a separatory funnelalong with CH₂ Cl₂. The solution was washed with water and brine. Theorganic phase was dried over anhydrous Na₂ SO₄. Filtered andconcentrated to a glassy residue that was purified by recrystallizationfrom CH₂ Cl₂ /Et₂ O. Isolated 198 mg of the desired product as a whitesolid. mp=128°-129° C. Aqueous solubility (pH 7, phosphate buffer) was79.1 mg/ml.

EXAMPLE 14 Acetic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylester, (S)

A solution of the trifluoroacetic acid salt of difluoropiperazineoxazolidinone (preparation in Ex. 15, below) (0.454 g, 0.969 mmol) andpotassium carbonate (0.159 g, 2.27 mmol) in 3 ml of methylene chloridewas cooled to 0° C. under nitrogen atmosphere. Acetoxyacetyl chloride(0.125 ml, 1.16 mmol) was then added in a dropwise fashion over 3 minvia syringe. The solution was allowed to gradually warm to roomtemperature as it stirred for 48 hours. Residual starting material waspresent therefore more acetoxyacetyl chloride (0.1 ml, 0.93 mmol) wasadded and the reaction mixture was stirred for an additional 2.5 hrs.The reaction mixture was then filtered and evaporated to give 0.371 g ofcrude material which was subsequently purified on a silica column (40-63μ, 2.5×24 cm, packed and eluted with 5% methanol/ethyl acetate,collected 15 ml fractions) to give 0.107 g (24%) of the desired materialas a white solid, mp 193°-195° C., along with 0.096 g (28% recovery) ofthe difluoropiperazine oxazolidinone free base. Aqueous solubility (pH7, phosphate buffer) was 1.6 mg/ml.

EXAMPLE 15 Succinic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, (S)

Part 1 demonstrates the preparation steps for difluorointermediates ofthe invention.

Part 1

(a) 2,6-difluoro-4-nitrobenzene(trifluoromethane)sulfonate

2,6-Difluoro-4-nitrophenol (31.55 g, 180.19 mmol) was combined with CH₂Cl₂ (300 mL) and pyridine (29.15 mL, 360.38 mmol). The resultant slurrywas cooled to 0° C. in an ice bath and then treated dropwise withtriflic anhydride (31.8 mL, 189.2 mmol) over a period of 45 minutes. Thereaction was allowed to stir at 0° C. for two hours and then it wasstored in the refrigerator (5° C.) overnight. The reaction wasdetermined to be complete by TLC (15% EtOAc/hexane, UV short wave). Thereaction mixture was concentrated under reduced pressure, and thentreated with both H₂ O (50 mL) and EtOAc (50 mL). This mixture wastransferred to a separatory funnel with more EtOAc (100 mL) and washedwith 1N HCl until the washings were acidic (2×100 mL). The aqueousphases were back-extracted with EtOAc (2×200 mL). The combined EtOAcextracts were combined and then washed again with 1N HCl (400 mL) andonce with brine (400 mL). The organic phase was dried of over anhydrousNa₂ SO₄, filtered and then concentrated to yield 54.092 g of a red-goldoil. Although the oil was prue by NMR, it was combined with crudeproducts from two other runs and chromatographed over silica gel (500 g)packed with 5% EtOAc. Elution with 2 L each of 5% EtOAc and 10% EtOAcafforded a 95% overall yield of the title compound as a pale yellow oilwith HRMS (M⁺) calcd for C₇ H₂ F₅ NO₅ S 306.9574, found 306.9590.

(b) 1-(tert-butoxycarbonyl)-4-(2,6-difluoro-4-nitrophenyl)piperazine

A solution of 2,6-difluoro-4-nitrobenzene(trifluoromethane)sulfonate (55g, 179 mmol) in dry DMF (275 mL) was treated with1-(tert-butoxycarbonyl)piperazine (45.71 g, 250 mmol). The resultantclear yellow solution turned oragne upon the addition ofN,N-diisopropylethylamine (47 mL, 269 mmol). The reaction was heated toreflux for 15 hours under N₂. The reaction was determined to be completeby TLC (30% EtOAc/hexane, UV short wave). The reaction mixture wasconcentrated by dryness and combined with the crude product of anotherreaction for purification. The crude material was dissolved in hot CH₂Cl₂ (420 mL; some solids unrelated to the product did not dissolve) andthen chromatographed on three separate columns (2 columns with 750 gsilica gel, packed with CH₂ Cl₂, loaded with 180 mL material, and elutedwith 1 L each of 1-5% EtOAc/CH₂ Cl₂ ; one column with 250 g silica gelpacked with CH₂ Cl₂, loaded with 60 mL compound, and eluted with 2.5 and5% EtOAc/CH₂ Cl₂) to give an 87% yield of the title compound as anorange solid with HRMS (M⁺) calcd for C₁₅ H₁₉ F₂ N₃ O₄ 343.1343, found343.1358.

(c)1-(tert-butoxycarbonyl)-4-[2,6-difluoro-4-(benzyloxycarbonyl)aminophenyl]piperazine

The 1-(tert-butoxycarbonyl)-4-(2,6-difluoro-4-nitrophenyl)piperazine(44.7 g, 130 mmol) was dissolved in 20% THF/MeOH (600 mL) in a 2 Lflask. Ammonium formate (41 g, 651 mmol) was added portionwise, followedby 10% Pd-C (1.12 g, 2.5 weight %), with cooling in an ice bath. Whenthe addition was completed the ice bath was removed. The flask becameslightly warm, and the yellow color disappeared. The reaction mixturewas filtered through Celite (washing the filter cake with 500 mL MeOH).The filtrate was concentrated under reduced pressure to give a solidwhich was then treated with 1 L EtOAc and 500 mL H₂ O. The layers wereseparated and then the organic layer was washed again with H₂ O (500 mL)and once with brine (500 mL). The aqueous portions were back-extractedwith more EtOAc (2×300 mL). The combined organic extracts were driedover anhydrous Na₂ SO₄, filtered and concentrated to yield a yellowsolid. The crude material was recrystallized from hot EtOAc/hexane toafford 39.11 g (67%) of the title compound as a pale yellow crystallinesolid with mp 171°-172° C.

(d)[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methanol

The1-(tert-butoxycarbonyl)-4-[2,6-difluoro-4-(benzyloxycarbonyl)aminophenyl]piperazine(14.05 g, 31 mmol) was dissolved in dry THF (150 mL) and then cooled to-78° C. (dry ice/acetone). The reaction was next treated with withn-BuLi (21.6 mL, 35 mmol) dropwise over a 25 minute period. The reactionwas allowed to stir at -78° C. for 30 minutes and then(R)-(-)-glycidylbutyrate (4.89 mL, 35 mmol) was added dropwise over 7minutes. The reaction was maintained at -78° C. for an additional 15minutes and then the bath was removed, allowing the reaction to slowlywarm up to room temperature overnight. The reaction was determined to becomplete by TLC (5% MeOH/CHCl₃, UV short wave). The reaction mixture wasdiluted with 500 mL CH₂ Cl₂ and then washed with both H₂ O (3×300 mL)and brine (300 mL). The aqueous portions were back-extracted with moreCH₂ Cl₂ (3×400 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to give a creamy yellow solid. The crudesolid was purified by recrystallization from hot EtOAc/hexane to give11.063 g (85%) of the title compound as a white solid with mp 164°-166°C.

(e)[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-p-toluenesulfonate

The[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methanol(24.2 g, 59 mmol) was dissolved in pyridine (110 mL) and then cooled to0° C. (ice bath). Freshly recrystalized p-toluenesulfonyl chloride (13.4g, 70 mmol) of was added and the reaction was allowed to stir at 0° C.for 2.5 hours under N₂. The flask was then stoppered and stored in therefrigeratior (5° C.) overnight. The reaction mixture became a pale pinkslurry. TLC revealed that some alcohol still remained. The reactionmixture was treated with additional p-toluenesulfonyl chloride (1.12 g,5.85 mmol), catalytic 4-(dimethylamino)pyridine, and 20 mL of dry CH₂Cl₂ to facilitate stirring. After 4 hours at 0° C., the reaction wasfound to be complete by TLC (5% MeOH/CH₂ Cl₃, UV short wave). Themixture was added to 750 mL ice water and the precipitated productisolated via suction filtration, washing it with both water (1 L) andether (500 mL). After drying in vacuo, 29.921 g (90%) of the titlecompound was obtained as white solid with mp 150.5°-151.5° C.

(f)[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2oxo-5-oxazolidinyl]methyl]methanesulfonate

The[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methanol(3.831 g, 9.27 mmol) was dissolved in CH₂ Cl₂ (40 mL), cooled to 0° C.,and treated with triethylamine (1.74 g, 2.4 mL, 17.22 mmol) under N₂.Methanesulfonyl chloride (1.48 g, 1 mL, 12.92 mmol) was slowly addedover 1 min. TLC analysis (20% acetone/CH₂ Cl₂) after 0.5 h revealed thereaction to be complete. The reaction mixture was diluted with CH₂ Cl₂(200 mL) and washed with water (3×50 mL) and brine (50 mL), dried overNa₂ SO₄, filtered and concentrated in vacuo to furnish the titlecompound as an off-white solid with HRMS (M⁺) calcd for C₂₀ H₂₇ F₂ N₃ O₇S 491.1538, found 491.1543.

(g)[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]azide

The[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-p-toluenesulfonate(29.661 g, 52 mmol) was dissolved in dry DMF (125 mL) and then treatedwith solid NaN₃ (10.19 g, 156 mmol) at room temperature. The reactionwas heated to 60° C. for three hours and then allowed to cool to roomtemperature overnight under N₂. The reaction was found to be complete byTLC (30% EtOAc/hexane, run twice, UV short wave). The reaction mixturewas concentrated in vacuo to give a cream colored solid. The crudeproduct was dissolved in 600 mL EtOAc and then washed with both H₂ O(2×500 mL) and brine (500 mL). The aqueous portions were back-extractedwith more EtOAc (2×400 mL). The combined organic extracts were driedover Na₂ SO₄, filtered and concentrated in vacuo to yield 22.41 g (91%)of the title compound as a pale yellow solid with mp 115°-117° C.

Employing essentially identical conditions, the corresponding mesylatewas converted to the same azide.

(h)N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide

The[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5oxazolidinyl]methyl]azide(22.4 g, 51 mmol) was dissolved in 1 L of EtOAc and then degassed threetimes with N₂. Next, 10% Pd-C (4.48 g, 20% by weight) was added and thesolution was degassed again threee times (with N₂) before replacing theatmosphere with H₂ (balloon). After 3 hours, the reaction was determinedto be complete by TLC (20% MeOH/CHCl₃, UV short wave). At this point,pyridine (8.26 mL, 102 mmol) was added, followed by treatment withacetic anhydride (9.64 mL, 102 mmol). The reaction mixture was allowedto stir overnight at room temperature. The reaction was found to becomplete by TLC (20% MeOH/CHCl₃, UV short wave). The reaction mixturewas filtered through celite (the filter cake was washed with 500 mLEtOAc), the filtrate concentrated down to approximately 600 mL, andwashed with H₂ O (2×500 mL) and brine (500 mL). The aqueous portionswere back-extracted with more EtOAc (2×500 mL). The combined organicextracts were dried over anhydrous Na₂ SO₄, filtered and concentrated togive a yellow solid. Recrystallization of the crude product from hotCHCl₃ and hexane afforded 19.167 g (83%) of the difluoro title compoundas a white solid with mp 177°-179° C.

Part 2

(S)-N-[[3,[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(7.1 g, 15.6 mmol) was dissolved in CH₂ Cl₂ (20 mL) and then added to acold solution of trifluroracetic acid (24 mL). The reaction was allowedto stir at 0° C. under N₂ for 15 minutes, and then the ice bath wasremoved. After stirring at room temperature for 2 hours, the reactionwas complete by TLC (10% MeOH/CHCl₃, UV short wave). The solvent wasevaporated off in vacuo to give a gummy brown solid. This solid wasdissolved in 30% H₂ O/acetone, and then treated with the portion wiseaddition of NaHCO₃ (7.87 g, 93.7 mmol). The reaction was stirred at roomtemperature for 20 minutes and then the trifluoroacetate salt wastreated with benzyloxyacetyl chloride (3.70 mL, 23.4 mmol) added dropwise over 4 minutes. The reaction mixture was allowed to stir overnightunder N₂ at room temperature. The reaction mixture was transferred to aseparatory funnel with EtOAc (400 mL) and then washed with water (3×250mL), saturated NaHCO₃ (250 mL), and brine (250 mL). The aqueous portionswere back-extracted with both EtOAc and CH₂ Cl₂. The organic layers weredried over anhydrous NaSO₄, filtered and concentrated to yield a yellowsolid. The solid was adsorbed on silica gel (25 g) and thenchromatographed (200 g SG), eluting with a gradient of 1-4% MeOH in 10%CH₃ CN/CHCl₃ to give 5.85 g (75%) of(S)-N-[[3-[3,5-difluoro-4-[4-(benzyloxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideas a white solid with a melting point of 172°-173° C.

Next,(S)-N-[[3-[3,5-difluoro-4-[4-(benzyloxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(3.84 g, 7.6 mmol) was dissolved in hot 10% EtOac/MeOH (150 mL). Afterdegassing the solution three times with N₂, the Pearlman's catalyst (384mg, 10% by weight) was added. The solution was degassed again and thenthe atmosphere was replaced with H₂. The reaction was stirred at roomtemperature for 4.5 hours. At this point, the reaction was found to becomplete by TLC (10% MeOH/CHCl₃, UV short wave). The solution wasfiltered through celite, washing the cake with EtOAc (250 mL). Thefiltrate was concentrated under reduced pressure to give a white solid.The material was chromatographed on silica gel (150 g), eluting with agradient of 1-6, 10% MeOH in 10% CH₃ CN/CHCl₃ to yield 3.078 g (98%) of(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideas a white solid with a melting point of 160.5°-162.5° C.

The prepared product (0.247 g, 0.599 mmol), succinic anhydride (0.092 g,0.919 mmol) and 4-dimethylaminopyridine (0.024 g, 0.196 mmol) wereweighted into a flame dried flask. Pyridine (10 ml) was added and thesolution was placed under nitrogen atmosphere. After stirring 24 hrs thereaction was not complete, therefore more succinic anhydride (0.096 g,0.959 mmol) was added. The reaction mixture was stirred an additional 2hours at room temperature then was heated at reflux for 35 min. Thesolvent was then removed via bulb to bulb distillation to give the crudeproduct as a gummy oil. Water (35 ml) and methylene chloride (65 ml)were then added to the crude product, the phases were separted and theorganic portion was extracted with sat. sodium bicarbonate (35 ml). Thisaqueous portion was then acidified with 3M hydrochloric acid and wasextracted with ethyl acetate 3×35 ml. These organic portions werecombined, dried with MgSO₄, and evaporated to give the desired productwhich was still slightly contaminated with succinic acid as a whitesolid (0.169 g). Because of the low recovery the aqueous portion wasbasified with sat. sodium bicarbonate and extracted with methylenechloride (30 ml). The aqueous poriotn was again acidified with 3Mhydrochloric acid and was extracted with ethyl acetate (3×35 ml). Theorganics were then evaporated to give 0.161 g of white solid whichcontained the desired product and acetic and succinic acids. The firstbatch of product was purified by recrystallization from methanol to give0.120 g (39%) of white solid mp 143°-144° C. The second batch waspurified first by column chromatography (silica, 40×63 μ, 2 ml pipette,packed with 5% methanol/ethyl acetate, eluted with ethyl acetate, 5% and20% methanol/ethyl acetate, collected 2 ml fractions) then byrecrystallization from methanol and chloroform to give an additional0.078 g (25%) of the desired material as a white solid. Aqueoussolubility (pH 7, phosphate buffer) was 12.3 mg/ml.

EXAMPLE 6 Succinic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, sodium salt, (S)

The product from Ex. 15 was dissolved in 1 ml of 0.14M sodiumbicarbonate and 5 ml of water. This solution was then frozen andlyophilized to give 0.032 g (41%) of the desired material as a whitegum.

EXAMPLE 17 Succinic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, (S)

A pyridine solution (5 ml) of the Intermediate from Ex. 1 (0.267 g,0.677 mmol), succinic anhydride (0.075 g, 0.749 mmol), and4-dimethylaminopyridine was stirred for 6 days under nitrogenatmosphere. The reaction was then worked up even though there was stillstarting oxazolidinone present as indicated by tlc. The pyridine wasevaporated on the high vacuum, and the residue was taken up in ethylacetate (15 ml) and sat. sodium bicarbonate (35 ml). The phases wereseparted, the aqueous portion was acidified to pH 1 with 3M hydrochloricacid and was extracted with ethyl acetate (5×15 ml). These extractionswere combined, dried with MgSO₄ and evaporated to give 0.135 g of lightpink solid. Because of the low recovery, the aqueous portion wasextracted with more ethyl acetate (5×15 ml). These extracts were driedwith MgSO₄ and evaporated to give 0.177 g of white solid. The solidswere combined and subjected to another aqueous workup in order toupgrade the material. Thus, the solids were dissolved in 10 ml of sat.sodium bicarbonate and 15 ml of ethyl acetate. The phases were separtedand the aqueous portion was acidified with 3M hydrochloric acid, whichwas then extracted with ethyl acetate (5×10 ml). The organic portion wasdried with MgSO₄, and evaporated to give the desired product (0.130 g,39%) as a white solid, mp 67°-70° C. Aqueous solubility (pH 7, phosphatebuffer) was 28 mg/ml.

EXAMPLE 18 4-Oxo-valeric acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylester, (S)

(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperzinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(preparation described in Ex. 15) 0.178 g, 0.432 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (0.161 g,0.839 mmol), and 4-dimethylaminopyridine (0.007 g, 0.057 mmol) wereweighed into a flame dried flask. Pyridine (3 ml) was added and thesystem was placed under nitrogen atmosphere, the levulinic acid (0.07ml, 0.683 mmol) was added. After stirring for 5 days the pyridine wasevaporated on the high vacuum to give the crude material as a yellowoil. The quality of the crude material was upgraded on a samll column,(silica, 40×63 μ, 2 ml pipette, packed with ethyl acetate, eluted withmethylene chloride, ethyl acetate, and 5% methanol/ethyl acetate,collected 1 ml fractions). The quality was further improved on a secondcolumn (mp, silica, 40×63 μ, 1.5×27 cm, packed with ethyl acetate,eluted with ethyl acetate and 5% methanol/ethyl acetate, collected 20 mlfractions) to give white solid which was still slightly contaminated.This solid was recrystallized from ethyl acetate to give 0.152 g (69%)of the desired material as a white solid, mp 130°-133° C. Aqueoussolubility (pH 7, phosphate buffer) was 1.2 mg/ml.

EXAMPLE 19 4-Oxo-valeric acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, (S)

The intermediate from Ex. 1 (0.100 g, 0.253 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (0.091 g,0.475 mmol), and 4-dimethylaminopyridine (0.005 g, 0.041 mmol) wereweighed into a flame dried flask. Pyridine (3 ml) and levulinic acid(0.04 ml, 0.391 mmol) were added and the system was placed undernitrogen atmosphere. After stirring for 2 days the pyridine wasevaporated under high vacuum and the resulting residue was purified on asilica column (40×63 μ1.5×25 cm, packed with ethyl acetate, loaded withmethylene chloride and methanol, eluted with ethyl acetate and 5%methanol/ethyl acetate, collected 15 ml fractions) to give 0.136 g ofdesired product which was then recrystallized from ethyl acetate to give0.074 g (59%) of the desired material as a white solid, mp 135.5°-138°c. Aqueous solubility (pH 7, phosphate buffer) was 2.29 mg/ml.

EXAMPLE 20 Phosphoric acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylester, (S)

A solution of the Intermediate from Ex. 1 (200 mg, 0.51 mmol) in dryacetonitrile (20 mL) was cooled under nitrogen and treated with1H-tetrazole (Aldrich) with stirring. In a separte flask, dibenzylN,N-diethylphosphoramidite (483 mg, 1.52 mmol) was dissolved in 7 mL ofdry acetonitrile and was transferred via cannula to the reaction mixturewith stirring for 20 hours. The flask was cooled in an ice bath for 30minutes, and the mixture treated with m-chloroperoxybenzoic acid. After5 minutes, the ice bath was removed and the mixture stirred for 1.5hours after which the mixture was cooled to 0° C. and treated with asolution of 15 mg of sodium sulfite in 10 mL of pH 7 buffer. The mixturewas diluted with methylene chloride and extracted with water andsaturated sodium sulfite solution. The organic layer was dried (Na₂ SO₄)and concentrated in vacuo to afford a colorless oil. This material wassubjected to radial chromatograhy eluting with a methylenechloride-methanol system to afford 250 mg (75%) of the intermediate,phosphoric acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1piperazinyl)-2-oxoethylester, dibenylester, (S), as a white rigid foam. TLC: RF=0.51 (20:1Methylene chloride-methanol). Exact Mass: calc'd for C₃₂ H₃₆ FN₄ O₈ P:655.2333. Found 655.2347.

Next, a solution of the prepred intermediate, above, (350 mg, 0.54 mmol)was dissolved in 5 mL of methanol resulting in a clear, colorlesssolution with a small amount of undissolved amorphous solid material.The solution was treated with 100 mg of 10% palladium on carbon andhydrogen gas at atmosphere pressure for 16 hours. The mixture wasfiltered through celite washing the filter pad with methanol andconcentrated in vacuo to afford a rigid foam. This material wasdissolved in water, filtered and lyophilized to afford a white solid, mp119°-122° C. Aqueous solubility (pH 7, phosphate buffer) was 25.7 mg/ml.

EXAMPLE 21 4-aminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

To a mixture of 956 mg (2.426 mmol) the Intermediate from Ex. 1 and 0.7ml (5.03 mmol) triethylamine in 20 ml of methylene chloride was added553 mg (2.980 mmol) of 4-nitrobenzoyl chloride as a solid all at once.The mixture was stirred for 21.5 hours at room temperataure. After thistime, 10 ml of 1N HCl was added to the mixture and the layers wereseparated. The aqueous layer was extracted with methylene chloride (4×10ml). The combined organic layers were washed with brine and dried(MgSO₄) and concentrated in vacuo. The obtained foamy solids were takenup in methylene chloride and placed upon a 24 cm×2.5 cm 40-63 μ silicacolumn and eluted off with ethyl acetate (250 ml), 10%methanol/ethylacetate (250 ml), 20% methanol/ethylacetate (250 ml), and10% methanol/methylene chloride (250 ml). The appropriate fractions werepooled to provide 1.082 g of 4-nitrobenzoic acid,2-[4-[4-[5-[(acetylaminomethyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; as a yellow solid in 82% yield (mp=222°-224° C.).

Next, 845 mg (1.555 mmol) of this product and 460 mg of 10% palladium oncarbon was stirred in 100 ml of methanol/methylene chloride (1:1) underhydrogen (from a balloon) for 2 hours. The mixture was then filteredover diatomaceous earth and the filter pad washed with 70 ml ofmethanol/methylene chloride (1:1). The filtrate was concentrated invacuo to provide 765 mg (96% crude yield) of foamy solids. A 550 mgportion of the solids was taken up in methylene chloride and placed upona 9 cm×2.5 cm 70-230 mesh silica column. The column was eluted with 500ml of 10% methanol/ethylacetate. Upon partial concentration of thecombined fractions product was seen to precipitate. The precipitate wascollected ty vacuum filtration to provide 352 mg of a white solid. Asecond crop (29 mg) of this compound was obtained upon concentration thefiltrate. And concentration of the final filtrate provide 165 mg of thetitle compound as a glassy solid. In all 546 mg of the title compoundwas obtained from the column (99% recovery). The white solids became aglassy solid between 110° C. and 115° C. and a free flowing liquidat >215° C. Aqueous solubility (pH 7, phosphate buffer) was 0.03 mg/ml,although the salt version should be higher.

EXAMPLE 22 2,2-bis(hydroxymethyl)propionic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

A solution of 183 mg (0.46 mmol) of the Intermediate of Ex. 1 and 146 mg(0.46 mmol) of 2,2-bis(benzyloxymethyl)propionic acid in 5 mL ofpyridine was treated with 98 mg (0.51 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 57 mg (0.46 mmol) ofdimethylaminopyridine with stirring under nitrogen. After 72 h, thesolvent was evaporated in vacuo to afford a yellow oil which waschromatographed over silica gel eluting with a methylenechloride-methanol system. These procedures afforded 82 mg (26%) of awhite rigid foam. TLC: Rf=0.59 (20.1 methylene chloride-methanol).

A solution of this product 160 mg (0.23 mmol) of in 7 mL of methanol wastreated under nitrogen with 50 mg of 10% palladium on carbon andhydrogen gas at atmospheric pressure. After 16 h, the mixture wasfiltered through celite and concentrated in vacuo to afford a colorlessoil. This material was subjected to raidal chromatography eluting with amethylene chloride-methanol system to afford 99 mg (85%) of the desiredproduct as a white rigid foam. TLC: Rf=0.26 (20:1methylenechloride-methanol. Aqueous solubility (pH 7, phosphate buffer) was 13mg/ml.

EXAMPLE 23 Hydroxyacetic acid,2-[4-[4-[5[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)

To a mixture of 200 mg (0.508 mmol) of U-100592 (Ex. 1), 149 mg (1.47mmol, 0.205 mL), and 5 mL methylene chloride at 0° C.benzyloxyacetylchloride was added dropwise. The reaction was allowed towarm slowly up to room temperature. After stirring for 5 hours, 5 mL of1N HCl was added, and the resulting layers were separated. The aqueouslayer was extracted with methylene chloride (3×5 mL). The combinedorganic layers were washed with brine and dried (MgSO₄) then filteredand concentrated to a white solid. The crude was dissolved in a smallamount of methylene chloride and methanol and was placed on a 22 cm×2.5cm 40-60 μ silica column. The column was eluted with ethyl acetate, 2%methanol/ethylacetate, 4% methanol/ethyl acetate, 6% methanol/ethylacetate, 8% methanol/ethyl acetate, and 10% methanol/ethyl acetate (250mL each). The appropriate fractions were pooled to provide 120 mg (44%)of benzyloxyacetic acid,2-[-[4-[5-(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; as a white solid (mp=146°-148° C.).

A mixture of this product 170 mg (0.314 mmol), 15 mL methanol, 3 mLmethylene chloride, and 100 mg 10% palladium catalyst. The reactionflask was evacuated with hydrogen 3 times and was allowed to stir underhydrogen overnight. The reaction was filtered by vacuum filtration withfilter aid to remove the palladium catalyst and was concentrated toprovide 130 mg (93% yield) of the title compound (mp=105°-107° C.).Aqueous solubility (pH 7, phosphate buffer) was 4.2 mg/ml.

EXAMPLE 24 Hydroxyacetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester,

(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(preparation described in Ex. 15) was used to prepare benzyloxyaceticacid,2-[4-[4-[5[(acetylamino)methyl}-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-, in a 62% yield (mp=155°-157° C.) following the sameprocedure as for Example 23.

The subject compound was prepared from benzyloxyacetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2oxoethylester, (S)-; in a 76% yield (mp=106°-108° C.) following the sameprocedure as for Ex. 23.

EXAMPLE 25 Methoxyacetic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylester, (S)

The(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(263 mg, 0.67 mmol) was slurried in dry CH₂ Cl₂ (10 mL) and cooled to 0°C. in an ice bath. The soluton became homogeneous after the addition ofthe pyridine (0.216 mL, 2.67 mmol). Next, the methoxyacetyl chloride(0.064 mL, 0.69 mmol) was added drop wise. The reaction was stirred at0° C. for 30 minutes and then the ice bath was removed. After one hour,the reaction was found to be complete by TLC (10% MeOH/CHCl₃, UV shortwave). The reaction mixture was diluted with CH₂ Cl₂ (100 mL) and thenwashed with 1N HCl/brine (50 mL each), saturated NaHCO₃ /brine (50 mLeach), and brine (100 mL). Each aqueous portion was back-extracted withmore CH₂ Cl₂ (2×25 mL). The organic layers were combined, dried overanhydrous NaSO₄, filtered, and concentrated under reduced pressure togive an orange solid. This solid was chromatographed on silica gel (35g,) eluting with a gradient of 1-5% MeOH in 10% CH₃ CN/CHCl₃ to give anorange solid. The latter solid was recrystallized by dissolving it in aminimal amount of CH₂ Cl₂ /MeOH and then triturating with ether to yield158 mg (51%) of the title compound as an off-white solid with a meltingpoint of 147°-148° C. Aqueous solubility (pH 7, phosphate buffer) was6.4 mg/ml.

EXAMPLE 26 3-(N-morpholinyl)propionic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxaxzolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylester, (S)

(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(preparation described in Ex. 15), 250 mg (0.607 mmol) was dissolved in10 mL of pyridine. To this solution was added 13 mg of DMAP, 192 mg(1.21 mmol) 3-(N-morpholinyl)propionic acid and 232 mg (1.21 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Thereaction was allowed to stir at room temperature, under N₂ for 15 hours.After this time the reaction was complete and was concentrated in vacuo.The crude product was purified by silica gel chromatography (10 g ofsilica gel, eluted with 1-4% MeOH/ChCl₃). The recovered product (367 mg)contained a small amount of urea byproduct. A 250 mg portion of thismaterial was further purified by radial chromatography (eluted with1-66% MeOH/CHCl₃). After concentration, 210 mg of analytically pureproduct was recovered as a glassy, white solid. The title product (92%)was recovered as a glassy, white solid. mp: 139°-142° C.

FTIR(mull): cm⁻¹ 3450(br), 1754, 1665, 1514, 1450, 1247, 1120, 1032,836.

Anal: Calc'd for C₂₅ H₃₃ F₂ N₅ O₇ 1/3 H₂ O: C, 53.66; H, 6.02; N, 1252.Found: C, 53.66; H, 6.01; N, 12.55. Aqueous solubility (pH 7, phosphatebuffer) was 8.2 mg/ml.

MS(EI):m/z(rel. int.) 553[M⁺ ](1), 478(7), 229(19), 158(17), 100(66),56(53), 43(100). [α]=31 7° (c=9.67, CHCl₃).

EXAMPLE 27 (4-morpholinyl)acetic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylester, (S)

A solution of 140 mg (0.272 mmol) of U-103676 in 3 mL of dryacetonitrile was treated with 52 mg (0.598 mmol) of morpholine withstirring for 18 hours. The off-white solid. This material was subjectedto silica gel chromatrography eluting with a methanol-methylene chloridesystem to afford 115 mg (81%) of the desired product as a white solid.TLC: Rf=0.33 (20:1 Methylene chloride-methanol). Exact Mass: calc'd forC₂₄ H₃₂ FN₅ O₇ : 521.2286. Found: 521.2288. Aqueous solubility (pH 7,phosphate buffer) was 55.3 mg/ml.

EXAMPLE 28 4-N-(N,N-dimethylglycinyl)aminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

A mixture of 204 mg (01.398 mmol) of the title compound from Ex. 21,catalytic amount (<10 mg) of 4-dimethylamino pyridine (DMAP), 156 mg(0.814 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and 147mg (1.05 mmol) of temperature. The mixture was then concentrated invacuo. The obtained crude was treated with 5 ml saturated aqueous sodiumbicarbonate and 20 ml of water and extracted with methylene chloride(4×20 ml). The combined organic layers were washed with brine, dried(MgSO₄) and purified on a 23 cm×2.5 cm, 40-63 μ silica gel columneluting with 5% methanol/methylene chloride (1 L) to provide 175 mg(74%) of the desired product as foamy solids. Trituation with 10%methanol/ethylacetate of foamy solids from a different lot providedwhite solids with mp=180°-182° C. Aqueous solubility (pH 7, phosphatebuffer) was 0.09 mg/ml, although the salt version should be higher.

EXAMPLE 29 4-N-(glycinyl)aminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)- Step 1

A mixture of 100 mg (0.195 mmol) of the title compound from Ex. 21, 243mg (1.27 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and 269mg (1.29 mmol) of N-CBZ-glycine in 4.0 ml of pyridine with a catalyticamount (<10 mg) of 4-dimethylamino pyridine (DMAP), was stirred overnight at room temperature. The mixture was then concentrated in vacuoand the obtained crude was purified on a 23 cm×2.5 cm, 40-63 μ silicagel column eluting with a methanol:methylene chloride gradient (500 ml2.5% MeOH/CH₂ Cl₂, 500 ml 5% MeOH/CH₂ Cl₂, 500 ml 10% MeOH/CH₂ Cl₂) toprovide 135 mg (99%) of 4-N-(N-carbobenzyl-oxyglycinyl) aminobenzoicacid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (s)- as white solids. Analysis Calc.: C, 59.65; H, 5.29; N,11.93. Found: C, 59.37; H, 5.35; N, 11.54.

Step 2

A mixture of this product 275 mg (0.391 mmol) and 170 mg of 10%palladium on carbon in 75 ml methanol and 55 ml of methylene chloridewas stirred over night under hydrogen (balloon). The mixture was thenfiltered over diatomaceous earth and the filtrate concentrated in vacuo.The obtained solids were triturated with methanol in a warm water baththen the mixture was cooled and the solids were collected by vacuumfiltration to provide 211 mg (95% yield) of the desired product as offwhite solids (mp 240° C. decomposition). Aqueous solubility (pH 7,phosphate buffer) was 9.8 mg/ml.

EXAMPLE 30 Acetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-

A mixture of 519 mg of the Intermediate from Ex. 1 in 2.5 ml aceticanhydride and 10 ml pyridine was stirred at room temperature for 2 hr.The mixture was concentrated in vacuo to a white solid, and this waspurified on a 24.5 cm×2.5 cm, 40-63 μ silica gel column, eluting with500 ml of 10% methanol/ethylacetate and 400 ml 15% methanol/ethylacetate(25 ml fractions). The appropriate fractions were pooled andconcentrated in vacuo to provide 540 mg (94%) of the title compound as afoamy white solid. The solid was triturated with 15 ml of 10%methanol/ethylacetate and the solids were collected by vacuum filtrationand dried in a vacuum oven to provide 436 mg (76%) of the title compoundas a fine white powder (mp=199°-201° C.)

What is claimed:
 1. A compound of structural Formula I: ##STR2## orpharmaceutically acceptable salts thereof wherein: R is --C(O)--R¹,--PO₃.sup.═ or --P(O)(OH)₂ :R¹ is C₁₋₆ alkyl, --N(R⁴)₂, C₁₋₆alkyl-N(R⁴)₂, -phenyl-N(R⁴)₂, -phenyl-NCH(O)CH₂ NH₂, --C₂ H₄-morpholinyl, pyridinyl, C₁₋₆ alkyl-OH, C₁₋₆ alkyl-OCH₃, C₁₋₆ alkylC(O)CH₃, --O--C₁₋₆ alkyl-OCH₃, C₀₋₃ alkyl-piperazinyl (optionallysubstituted with C₁₋₃ alkyl), imidazolyl, C₁₋₆ alkyl-COOH, --C(CH₂ OH)₂CH₃ ; R² and R³ are independently selected from hydrogen or F except atleast one of R² or R³ is F; R⁴ are independently selected from hydrogenor C₁₋₆ alkyl.
 2. The compound of claim 1 wherein R is --C(O)--R¹. 3.The compound of claim 2 wherein R¹ is --CH₃, --CH₂ N(CH₃)₂, --C₂ H₄ --morpholinyl or --CH₂ OH.
 4. The compound of claim 1 wherein R is--P(O)(OH)₂.
 5. The compound of claim 1 wherein R is --PO₃.sup.═.
 6. Thecompound of claim 1 which is an optically pure enantiomer having the S-configuration at C5 of the oxazolidione ring.
 7. The compound of claim 1wherein one of R² and R³ is F and the other is hydrogen.
 8. The compoundof claim 1 which is:1) 3-(4-Morpholinyl)propionic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-flurophenyl)-1-piperazinyl)-2-oxoethylester, (S); 2) Nicotinic acid,2-[4-[4-5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 3) Nicotinic acid2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 4) 1H-imidazole-1-carboxylic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 5) 1H-imidazole-1-carboxylic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 6) Carbonic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester-2-methoxyethyl ester, (S); 7) 4-dimethylaminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 8) 4-dimethylaminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 9) Glycine, N,N-dimethyl-,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 10) Glycine, N,N-dimethyl-,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 11) 3-(Dimethylamino)propanoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 12) 4-(Dimethylamino)butanoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 13) (4-Methyl-1-piperazinyl)acetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 14) Acetic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolindinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylester, (S); 15) Succinic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, (S); 16) Succinic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, sodium salt (S); 17) Succinic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, (S); (18) 4-Oxo-valeric acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylester, (S); 19) 4-Oxo-valeric acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylmonoester, (S); 20) Phosphoric acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylester, (S); 21) 4-aminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 22) 2,2-bis(hydroxymethyl)propionic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 23) Hydroxyacetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S); 24) Hydroxyacetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; 25) Methoxyacetic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinyl)-2-oxoethylester, (S); 26) 3-(N-morpholinyl)propionic acid,2-(4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2,6-difluorophenyl)-1-piperazinyl)-2-oxoethylester, (S); 27) 4-N-(glycinyl)aminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-; or 28) Acetic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S)-.
 9. A method for treating microbial infections in warmblooded animals comprising:administering to a patient in need thereof apharmaceutically effective amount of a compound of Formula I.
 10. Themethod of claim 9 wherein said compound is administered in an effectiveamount of from about 0.1 to about 100 mg/kg of body weight/day.
 11. Themethod of claim 10 wherein said compound is administered in an amount offrom about 3.0 to about 50 mg/kg of body weight/day.
 12. A compoundselected from the group consisting of:(4-morpholinyl)acetic acid,2-(4-(4-(5-((acetylamino)methyl-2-oxo-3oxazolidinyl-2-fluorophenyl)-1-piperazinyl)-2-oxoethylester, (S); and 4-N-(N,N-dimethylglycinyl)aminobenzoic acid,2-[4-[4-[5-[(acetylamino)methyl]-2oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethylester, (S).